The Section on Molecular Neuroscience studies the molecular mechanisms of chemically coded ionotropic and metabotropic neurotransmission in the nervous system. The ultimate goals of the project are identifying molecular components of synaptic transmission, and how these components are regulated to allow short-term and long-term information to be encoded within postsynaptic neurons and neuroendocrine cells. With regard to slow transmission by neuropeptides, we believe that neuropeptides may occupy a special evolutionary niche for nervous system adaptation to paraphysiologicalIy stressors, and that by studying their roles in stress physiology, we might uncover roles (and treatments) relevant to human disease. In 2004-2005, we continued to explore the role of the neuropeptide PACAP as an emergency response peptide in metabolic stress, stroke, circadian adaptation, and cerebellar development. Publications following from this work are listed in this report. Briefly, we have 1. identified the domain of the PAC1 receptor responsible for coupling to voltage-gated calcium channels, a mechanism through which PACAP subserves the adrenomedullary stress response, 2. demonstrated a novel form of cholinergic and noradrenergic co-transmission in the same peripheral autonomic neurons, and particular to the human/primate nervous system, 3. characterized a pathway for neuropeptide signaling that that involves gene regulation initated by cyclic AMP but not involving protein kinase A (non-canonical cAMP signaling) and relevant to neuronal differentiation, and 4. fully characterized a calcium-response element on the VIP gene that can function independently of that gene but synergistically with cAMP response elements to effect combinatorial signaling in neuroendocrine cells. We have also advanced our work, in collaboration with the Gillette lab, in demonstrating that PACAP is responsible for late-night phase advance in the circadian pacemaker of the hypothalamus, an important addition to the understanding of this system. Our aim in the coming year will be to identify PACAP-responsive genes in addition to the VIP gene that transduce these PACAP signaling in vivo and may represent targets for therapy in stroke, metabolic syndrome and circadian maladies.